#81 FLEA

SYNTHESIS: (from 3,4-methylenedioxyphenylacetone) A solution of 2.1 g
N-methylhydroxylamine hydrochloride and 4.4 g
3,4-methylenedioxyphenylacetone in 5.5 mL MeOH was added to a
suspension of 4.5 g NaHCO3 in 30 mL boiling MeOH. There was added
about 5 mL H2O (which gave a clear solution) followed by another 50 mL
H2O which produced a pale yellow color. To this solution of the
unisolated nitrone there was added 1.7 g sodium cyanoborohydride,
which generated a goodly amount of foaming. There was HCl added as
needed to maintain the pH at about neutrality. The reaction appeared
to have stopped after a day or two, so all was poured into 500 mL H2O,
acidified with HCl, and washed with 2x75 mL CH2Cl2. The addition of
base brought the pH >9, and this was then extracted with 3x75 mL
CH2Cl2. Removal of the solvent from the pooled extracts gave a
residue of 1.65 g of crude
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine. Efforts to obtain
solid seed samples of the salts with hydrochloric acid, perchloric
acid, sulfuric acid, phosphoric acid, and with a number of organic
acids, all failed. The salt formation from this free-base will be
discussed below.

(from MDOH) A solution of 0.75 g crystalline free-base MDOH in a few
mL MeOH was treated with a solution of 0.4 g sodium cyanoborohydride
in 10 mL MeOH, and there was then added 2 mL of 35% formaldehyde. The
stirred reaction mixture was kept at a neutral pH with the occasional
addition of HCl. After several days (when additional acid was no
longer required) the excess solvent was removed under vacuum, and the
residue poured into dilute H2SO4. This was washed with 2x75 mL CH2Cl2
and then, following the addition of base, this was extracted with 3x75
mL CH2Cl2. Removal of the solvent from the pooled extracts gave a
viscous oil residue of 0.53 g. The free-base product from these
preparations was distilled at 110-120 °C at 0.2 mm/Hg to give the
N-hydroxy-N-methyl product as a white oil. An alternate methylation
procedure used a solution of MDOH in a 4:1 MeOH/acetic acid solution
containing formaldehyde which was reduced with sodium borohydride at
dry ice temperatures. Its work-up is identical to that involving
sodium cyanoborohydride.

The distilled product was dissolved in an equal volume of MeOH, and
treated with a half-equivalent of oxalic acid dihydrate, dissolved in
10 volumes of MeOH. This combination gave the slow deposition of
crystals of the full oxalate salt (one acid, two bases) as a white
crystalline product. The mp of the crude salt was in the 130-150 °C
range, and after recrystallization from CH3CN,
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine oxalate (FLEA) had a
mp of 146-147 °C.

DOSAGE: 100 - 160 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 90 mg) The material tastes terrible, like
grapefruit juice that has stayed in the can too long. There was no
nausea, no feeling of difficulty in swallowing at any time during the
day. I felt a dry mouth and was thirsty--sipped water throughout the
day. At the beginning of the experiment, there was a glimmer of the
MDMA warmth, but later I felt separated and a bit isolated. I was
just floating around, seeing the beauty of colors and objects in the
house and outdoors and listening first to this conversation, then to
that one. All senses seemed enhanced. I found the material pleasant.
I was happy with the amount I took but would not be afraid to take
more or to take a supplement. I found it similar to, but not the same
as, MDMA.

(with 110 mg) We found this very similar to MDMA, but perhaps
slightly slower. I plateau'd at 2:30 hours and had a very gradual
descent. My friend had a marvelous and private 'cone of silence' that
was to him unique to MDMA or to 2C-T-8. Teeth problems were minor,
and the descent from the top of the experience showed less
interactive, and more contemplative action, than with MDMA. Very
similar to MDMA, but with its own character.

(with 110 mg) The onset was at about a half-hour. The come-on was
more gradual and much easier than with MDMA, and it seemed to be more
head than body oriented. I had about two hours of very complex and
personal self-evaluation, and I am not at peace in putting all of it
down here in writing. Overall I like it, and I would be interested to
see if there's a difference in conjunction with MDMA. Thanks very
much.

(with 110 mg + 35 mg) I saw my onset at 20 minutes, and it was
subtle, and very pleasant, and had a mild amphetamine-like elevation
for me (body lightness, cognitive functions seemed clear and clean,
heightened visual awareness and with some enhancement of color). It
seemed as if I were on the fringe of LSD-like visual changes, but that
never materialized. The affect was very good, communicative,
friendly, accepting, but without the profound emotional bonding of
MDMA. The following day felt very much like a post-LSD day; we felt
great. The body was light, energy good, emotions high, several
insights throughout the day, interactions clear and open--a
magnificent gift of a day. I started a menstrual period the day of
the experience and it lasted 6 to 7 days; all of this was a couple of
weeks early. I have a very favorable impression of FLEA although the
body penalty seems high.

EXTENSIONS AND COMMENTARY: Most people who were involved with the
evaluation of FLEA quite logically compared it with MDMA, as it was
presented as being a very close analogue which might share some of the
latter's properties. And to a large measure, the comparison was
favorable. The dosages are almost identical, the chronological course
of action is almost identical, and there are distinct similarities in
the effects that are produced. If there is a consensus of
similarities and differences it would be that it is not quite as
enabling in allowing a closeness to be established with others. And
perhaps there is more of a move towards introspection. And perhaps a
slightly increased degree of discoordination in the thought processes.
But also, part of this same consensus was that, were MDMA unknown,
this material would have played its role completely.

And from the scientific point of view, it lends more weight to a
hypothesis that just might be a tremendous research tool in
pharmacology. I first observed the intimate connection between an
amine and a hydroxylamine with the discovery that N-hydroxy-MDA (MDOH)
was equipotent and of virtually identical activity to the
non-hydroxylated counterpart (MDA). And I have speculated in the
recipe for MDOH about the possible biological interconversions of
these kinds of compounds. And here, the simple addition of a hydroxyl
group to the amine nitrogen atom of MDMA produces a new drug that is
in most of its properties identical to MDMA. The concept has been
extended to 2C-T-2, 2C-T-7, and 2C-T-17, where each of these three
active compounds was structurally modified in exactly this way, by the
addition of a hydroxyl group to the amine nitrogen atom. The results,
HOT-2, HOT-7 and HOT-17 were themselves all active, and compared very
closely with their non-hydroxylated prototypes.

Just how general might this concept be, that an N-hydroxyl analog of
an active amine shall be of similar action and duration as the parent
drug? What if it really were a generality! What havoc it would wreak
in the pharmaceutical industry! If I could patent the concept, then I
would be able to make parallel best sellers to all of the primary and
secondary amines out there in the industry. Perhaps 90% of all the
commercially available drugs that are concerned with the human mental
state are amines. And a goodly number of these are primary or
secondary amines. And each and every one of these could be converted
to its N-hydroxyl analogue, effectively by-passing the patent
protection that the originating corporation so carefully crafted. An
example, just for fun. A run-away best seller right now is an
antidepressant called fluoxetine, with the trade name Prozac. I will
make a small wager that if I were to synthesize and taste
N-hydroxy-N-methyl-3-phenyl-3-((a,a,a-trifluoro-p-tolyl)oxy)propylamine,
I would find it to be an active antidepressant. Remember, Mr. Eli
Lilly and Company; you read about it first, right here!

Of course, I was asked, why call it FLEA? The origin was in a classic
bit of poetry. A commonly used code name for MDMA was ADAM, and I had
tried making several modest modifications of the MDMA structure in the
search for another compound that would maintain its particular music
without the annoying tooth-grinding and occasional nystagmus, or
eye-wiggle, that some users have mentioned. One of these was the
6-methyl homologue which was, with some perverse logic, called MADAM.
And, following this pattern, the 6-fluoroanalogue was to be FLADAM.
So, with the N-hydroxy analogue, what about HADAM? Which brought to
mind the classic description of Adam's earliest complaint, an
infestation of fleas. The poem was short and direct. "Adam had 'em."
So, in place of HAD 'EM, the term FLEA jumped into being.